Liver cancer is the sixth most common cancer worldwide, affecting about 24 individuals in every 100,000 people a year. Hence, the current lack of therapeutic options for it is a grave concern. Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer occurrence. The lack of effective therapeutic interventions for HCC has also made liver cancer the second leading cause of cancer death worldwide. In most percentage of liver cancers, an identifiable gene mutation is present. Current drugs, such as sorafenib and regorafenib, used to treat HCC are not durable, and are typically only used to treat patients with advanced-stage HCC. Advances in therapeutic discovery for HCC are needed to address this unmet need. Scientists from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore, and the Agency for Science, Technology and Research (A*STAR)’s Genome Institute of Singapore (GIS) have discovered four potential drug compounds that target HCC, the most common type of liver cancer. The findings, which were made using a cancer gene-targeting drug-screening platform engineered by the team, are expected to pave the way for new and more effective treatments for liver cancer as well as other cancers.
With the development of the drug-screening platform, this study aims to address that concern by providing a more efficient drug discovery process. In addition, their discovery of potential drug compounds could pave the way for more effective and personalised liver cancer treatments in the future. The research team therefore developed a cancer gene-targeting drug-screening platform which tapped on libraries of synthetic molecules and natural compounds, to identify potential drug candidates against SALL4, a cancer gene linked to HCC. These drug candidates can address the unmet medical need for more effective treatments of HCC. The team found four natural compounds which target SALL4, which is a protein critical for early embryonic development but it is typically silenced in adult tissues. The protein, however, has been found to be reactivated in various cancers and is also expressed in 30 to 50% of HCC tumors. These natural compounds could potentially limit SALL4-linked HCC cancer cell growth. A probe into these compounds revealed that they are inhibitors of oxidative phosphorylation, a metabolic pathway that promotes the growth of cancer cells with high SALL4 expression.
A screening on over 1500 small molecules and a chembank of more than 21,000 natural compounds, yielded only four active candidates. The most potent natural compound identified, oligomycin, had a higher efficacy than existing standard-of-care drug sorafenib in preclinical studies, and displayed little toxicity at effective doses. Oligomycin is produced by streptomyces bacteria and has been used as a lab tool to study ion movements inside cells and mitochondria metabolism. When combined with sorafenib, oligomycin could further reduce the growth of SALL4-linked HCC tumors in vivo. Oligomycin may also be used to suppress other SALL4-linked cancers such as lung cancer. The findings also collectively suggest that SALL4 serves as a potential biomarker for clinicians to select cancer patients who could benefit from therapies involving oxidative phosphorylation inhibitors that disrupt the metabolism of certain tumor types. Moving forward, the team plans to further develop the oxidative phosphorylation inhibitors discovered for clinical testing in cancer patients, with the hope of bringing a more effective treatment option to patients with SALL4-linked cancers.
The team also aims to expand their innovative drug-screening platform to apply this knowledge for different cancer types. Prof Patrick Tan, Executive Director of GIS and Senior Principal Investigator at CSI, said: “Our study has identified a vulnerability in tumors that express cancer gene SALL4, as well as compounds targeting this vulnerability. These compounds have great potential to be further developed into drugs to effectively treat liver cancer and other cancers linked to this gene. Further studies on these compounds can lend deeper insights to bring advancement to precision medicine for SALL4-linked cancers, and to improve the quality of cancer treatments”. The study was conducted in collaboration with Brigham and Women’s Hospital, Boston, and the Harvard Medical School, and its findings were published in the scientific journal Gastroenterology.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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